Exploring the brain-eye connection: MRI-visible perivascular spaces, intraocular pressure and tau
Poster No:
2098
Submission Type:
Abstract Submission
Authors:
Merel van der Thiel1,2,3, Nienke van de Sande2,4, Anouk Meeusen1, Gerhard Drenthen1,2, Alida Postma1,2, Rudy Nuijts2,4, Noa van der Knaap1,2,5, Inez Ramakers2,3, Carroll Webers2,4, Walter Backes1,2,6, Marlies Gijs2,4, Jacobus Jansen1,2,7
Institutions:
1Department of Radiology & Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands, 2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands, 3Department of Psychiatry & Neuropsychology, Maastricht University, Maastricht, Netherlands, 4University Eye Clinic, Maastricht University Medical Center, Maastricht, Netherlands, 5Department of Intensive Care, Maastricht University Medical Center, Maastricht, Netherlands, 6Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands, 7Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands
First Author:
Merel van der Thiel
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Department of Psychiatry & Neuropsychology, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands|Maastricht, Netherlands
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Department of Psychiatry & Neuropsychology, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands|Maastricht, Netherlands
Co-Author(s):
Nienke van de Sande
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
Anouk Meeusen
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center
Maastricht, Netherlands
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center
Maastricht, Netherlands
Gerhard Drenthen
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands
Alida Postma
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands
Rudy Nuijts
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
Noa van der Knaap
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Department of Intensive Care, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands|Maastricht, Netherlands
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Department of Intensive Care, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands|Maastricht, Netherlands
Inez Ramakers
School for Mental Health and Neuroscience, Maastricht University|Department of Psychiatry & Neuropsychology, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands
School for Mental Health and Neuroscience, Maastricht University|Department of Psychiatry & Neuropsychology, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands
Carroll Webers
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
Walter Backes
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Cardiovascular Research Institute Maastricht, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands|Maastricht, Netherlands
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Cardiovascular Research Institute Maastricht, Maastricht University
Maastricht, Netherlands|Maastricht, Netherlands|Maastricht, Netherlands
Marlies Gijs
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
School for Mental Health and Neuroscience, Maastricht University|University Eye Clinic, Maastricht University Medical Center
Maastricht, Netherlands|Maastricht, Netherlands
Jacobus Jansen
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Department of Electrical Engineering, Eindhoven University of Technology
Maastricht, Netherlands|Maastricht, Netherlands|Eindhoven, Netherlands
Department of Radiology & Nuclear Medicine, Maastricht University Medical Center|School for Mental Health and Neuroscience, Maastricht University|Department of Electrical Engineering, Eindhoven University of Technology
Maastricht, Netherlands|Maastricht, Netherlands|Eindhoven, Netherlands
Introduction:
The cerebral waste clearance system (CWCS) is vital for maintaining healthy homeostasis and is compromised in neurodegenerative conditions,[1] including Alzheimer's disease (AD)[2]. Waste removal is conducted through perivascular spaces (PVS)[3]. Preclinical research suggests the existence of a similar system in the eyes: the ocular glymphatic system (OGS) (Fig.1)[4,5] The intraocular pressure (IOP) drives waste products from the eye through the optic nerve[6,7] into the CWCS.[4,8,9] However, human studies are scarce.[10]
In humans, CWCS function can be quantified with MRI-visible PVS.[11] Ultra-high field 7T MRI enables precise quantification of PVS enlargement.[12] Combining this with a measure for the driver of the OGS (i.e., IOP), provides a unique opportunity to explore connections between the eye and brain clearance systems.
Furthermore, this eye-brain connection may also offer a means to gather insights about brain pathology. Tear fluid analysis was shown to be feasible to determine tear total-tau (T-tau) concentration (a marker for AD pathology),[13] which was suggested as a proxy for cerebral tau presence and potentially indicatory of reduced CWCS.
This study aimed to uncover eye-brain connections by examining PVS and T-tau in healthy elderly and explore the connection between IOP and PVS, which could support the potential presence of an OGS in humans.
In humans, CWCS function can be quantified with MRI-visible PVS.[11] Ultra-high field 7T MRI enables precise quantification of PVS enlargement.[12] Combining this with a measure for the driver of the OGS (i.e., IOP), provides a unique opportunity to explore connections between the eye and brain clearance systems.
Furthermore, this eye-brain connection may also offer a means to gather insights about brain pathology. Tear fluid analysis was shown to be feasible to determine tear total-tau (T-tau) concentration (a marker for AD pathology),[13] which was suggested as a proxy for cerebral tau presence and potentially indicatory of reduced CWCS.
This study aimed to uncover eye-brain connections by examining PVS and T-tau in healthy elderly and explore the connection between IOP and PVS, which could support the potential presence of an OGS in humans.
Methods:
MRI acquisition: Thirty elderly subjects (mean age=66.9, 14F) underwent 7T MRI (Siemens Healthineers, Germany), including T1- and T1-weighted scans (Fig.2).
Ocular measures: Bi-ocular tear fluid was collected using Schirmer's strips while recording the tear-wetting length and analysed for T-tau (S-PLEX).[13] In 23 subjects, the average IOP per eye was calculated over three tonometer measurements.[14]
PVS scoring: PVS were scored on the T2-weighted images in the basal ganglia (BG) and centrum semiovale (CSO), two regions known for PVS occurrence.[11] Each hemisphere was scored in the slice with most PVS using a visual rating scale: 0 (<10), 1 (10-25), 2 (25-40), or 3 (>40).[11] Two blinded raters performed consensus scoring.
Anatomical brain size: White matter (WM) and BG volumes were automatically segmented on the T1-weighted images using Freesurfer (v6.0.5).[15]
Statistics: Partial Spearman's correlations were determined between PVS scores and both T-tau and IOP, while adjusting for age, sex, and tear-wetting length. To adjust for atrophy effects, significant associations were further adjusted for the respective hemispheric WM or BG volumes.
Ocular measures: Bi-ocular tear fluid was collected using Schirmer's strips while recording the tear-wetting length and analysed for T-tau (S-PLEX).[13] In 23 subjects, the average IOP per eye was calculated over three tonometer measurements.[14]
PVS scoring: PVS were scored on the T2-weighted images in the basal ganglia (BG) and centrum semiovale (CSO), two regions known for PVS occurrence.[11] Each hemisphere was scored in the slice with most PVS using a visual rating scale: 0 (<10), 1 (10-25), 2 (25-40), or 3 (>40).[11] Two blinded raters performed consensus scoring.
Anatomical brain size: White matter (WM) and BG volumes were automatically segmented on the T1-weighted images using Freesurfer (v6.0.5).[15]
Statistics: Partial Spearman's correlations were determined between PVS scores and both T-tau and IOP, while adjusting for age, sex, and tear-wetting length. To adjust for atrophy effects, significant associations were further adjusted for the respective hemispheric WM or BG volumes.
Results:
Elevated T-tau correlated significantly with higher CSO PVS scores in both hemispheres (Fig.2).
Lower right IOP was significantly correlated with higher right hemispheric CSO PVS scores, and a similar significant association was found between the left IOP and left hemispheric CSO PVS scores (Fig.2).
No other significant associations were found.
Lower right IOP was significantly correlated with higher right hemispheric CSO PVS scores, and a similar significant association was found between the left IOP and left hemispheric CSO PVS scores (Fig.2).
No other significant associations were found.
Conclusions:
Elevated T-tau was linked to more PVS in the CSO in both hemispheres, suggesting that elevated T-tau might signify cerebral waste accumulation due to impaired clearance.
This relationship was specific to the CSO, where PVS enlargement is associated with pathological protein deposition,[11] as opposed to the BG, where its more likely influenced by vascular changes.[11,16]
Lower IOP was associated with more PVS in the ipsilateral CSO, in line with the presence of an OGS in humans. Reduced IOP may hinder waste-containing fluid flow through the optic nerve to the CWCS (Fig.1).[6]
Notably, this relation was found ipsilaterally, but not contralaterally. This may be explained by the posterior pressure that is exerted on the fluid surrounding the optic nerve into the ipsilateral hemisphere, regardless of the optic nerve's crossing at the chiasm.
While alternative indirect pathophysiological explanations for the IOP-PVS connection should be considered, our exploratory results suggest that a reduction in the pressure driving the OGS relates to impaired CWCS, bridging the gap between these two systems.
This relationship was specific to the CSO, where PVS enlargement is associated with pathological protein deposition,[11] as opposed to the BG, where its more likely influenced by vascular changes.[11,16]
Lower IOP was associated with more PVS in the ipsilateral CSO, in line with the presence of an OGS in humans. Reduced IOP may hinder waste-containing fluid flow through the optic nerve to the CWCS (Fig.1).[6]
Notably, this relation was found ipsilaterally, but not contralaterally. This may be explained by the posterior pressure that is exerted on the fluid surrounding the optic nerve into the ipsilateral hemisphere, regardless of the optic nerve's crossing at the chiasm.
While alternative indirect pathophysiological explanations for the IOP-PVS connection should be considered, our exploratory results suggest that a reduction in the pressure driving the OGS relates to impaired CWCS, bridging the gap between these two systems.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 2
Lifespan Development:
Aging
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems 1
Novel Imaging Acquisition Methods:
Anatomical MRI
Physiology, Metabolism and Neurotransmission :
Cerebral Metabolism and Hemodynamics
Keywords:
Aging
Cerebro Spinal Fluid (CSF)
Degenerative Disease
HIGH FIELD MR
Neurological
NORMAL HUMAN
STRUCTURAL MRI
Systems
Other - perivascular space; waste clearance; ocular; eye
1|2Indicates the priority used for review
Provide references using author date format
2. Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain—implications for Alzheimer disease. Nature Rev Neurol. 2015;11(8):457-470.
3. Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. The glymphatic system: a beginner’s guide. Neurochemical research. 2015;40(12):2583-2599.
4. Wang X, Lou N, Eberhardt A, et al. An ocular glymphatic clearance system removes β-amyloid from the rodent eye. Science transl med. 2020;12(536).
5. Mathieu E, Gupta N, Ahari A, Zhou X, Hanna J, Yücel YH. Evidence for cerebrospinal fluid entry into the optic nerve via a glymphatic pathway. Invest ophthal & visual science. 2017;58(11):4784-4791.
6. Denniston A, Keane P. Paravascular Pathways in the Eye: Is There an 'Ocular Glymphatic System'? Invest ophthal & visual science. 2015;56:3955-3956.
7. Wostyn P, Van Dam D, Audenaert K, Killer HE, De Deyn PP, De Groot V. A new glaucoma hypothesis: a role of glymphatic system dysfunction. Fluids and Barriers of the CNS. 2015;12:1-6.
8. Uddin N, Rutar M. Ocular lymphatic and glymphatic systems: implications for retinal health and disease. Internat Journal of Molecular Sciences. 2022;23(17):10139.
9. Xu Y, Cheng L, Yuan L, Yi Q, Xiao L, Chen H. Progress on Brain and Ocular Lymphatic System. BioMed Research International. 2022.
10. Jacobsen HH, Ringstad G, Jørstad ØK, Moe MC, Sandell T, Eide PK. The human visual pathway communicates directly with the subarachnoid space. Invest ophthal & visual science. 2019;60(7):2773-2780.
11. Wardlaw JM, Benveniste H, Nedergaard M, et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nature Rev Neurol. 2020;16(3):137-153.
12. Yu L, Hu X, Li H, Zhao Y. Perivascular spaces, glymphatic system and MR. Front Neurol. 2022;13:844938.
13. Gijs M, Ramakers IH, et al. Association of tear fluid amyloid and tau levels with disease severity and neurodegeneration. Scientific Reports. 2021;11(1):22675.
14. Forbes M, Pico G, Jr., Grolman B. A Noncontact Applanation Tonometer: Description and Clinical Evaluation. Arch of Ophthal. 1974;91(2):134-140.
15. Fischl B. FreeSurfer. Neuroimage. 2012;62(2):774-781.
16. van den Kerkhof M & van der Thiel MM, et al. Impaired damping of cerebral blood flow velocity pulsatility is associated with the number of perivascular spaces as measured with 7T MRI. JCBFM. 2023:0271678X231153374.